Currently, 25 different human amyloid diseases are known. These diseases include Creutzfeldt-Jakob disease, one of a number of transmissible spongiform encephalopathies, Huntington's disease, amyotrophic lateral sclerosis, senile systemic amyloidosis, familial amyloid polyneuropathy, Kennedy disease, and Machado-Joseph Disease. Amyloidosis is characterized by aggregation of proteins and/or peptides, and each different amyloid disease appears to result from partial unfolding and refolding of a particular protein or peptide into an amyloidogenic intermediate, such as the partial unfolding and refolding of the well-known prion protein PrPC into the amyloidogenic intermediate PrPSC, which then aggregates to form larger structures, including fibrils and deposits. Molecular dynamics (“MD”) computational simulations of native-conformation and amyloidogenic-intermediate proteins and peptides have revealed that many of the amyloidogenic-intermediate proteins and peptides exhibit an unusual secondary structure referred to as α-sheet, described in a subsequent section of this document. It has been proposed that regions of α-sheet or extended α-strand within amyloidogenic intermediates provide inter-protein or inter-polypeptide binding sites that allow the soluble amyloidogenic intermediates to aggregate into polymer-like protofibrils and fibrils, which can, in turn, then aggregate into larger, insoluble structures, such as the plaques observed in the brain tissue of patients suffering from various spongiform encephalopathies. The extended-α-strand secondary structure has been only rarely observed in non-amyloidogenic protein structures, and α-sheet secondary structure has not been observed in non-amyloidogenic protein structures, but MD simulations have revealed extended-α-strand and α-sheet secondary structure in those amyloidogenic intermediates so far studied. As discussed below, the extended-α-strand and α-sheet secondary structure features an uncharacteristic dipole moment approximately orthogonal to the polypeptide backbone and features extended chains of carbonyl oxygens, on one side, and amide hydrogens, on the opposite side, both excellent targets for hydrogen bonding. The α-strand and α-sheet secondary structure may be only transiently exhibited during the amyloidosis process, amyloidogenic intermediates, and may transform to β-pleated sheet or other secondary-structure motifs as the conformation of protein and polypeptide monomers within higher-order aggregates, including fibrils and plaques, changes to more stable conformations within the higher-order aggregates.
Human amyloid diseases currently account for annual expenditure of over $100 billion in health care costs, and these costs are rising as more human amyloid diseases are clinically recognized. The costs of caring for those suffering from amyloid diseases may significantly rise with increasing rates of transmission of the transmissible forms of amyloidogenic intermediates, such as the infective prion protein PrPSC. Currently, there are no effective treatments or therapies for amyloid diseases, and the toll in human lives and in the disruptions in lives of family members, care-givers, and employers of those afflicted with amyloid disease is incalculable. Medical and scientific researchers, health care providers, government agencies, and, ultimately, those susceptible to amyloid diseases and those who care for victims of amyloid diseases have all recognized the need for medical therapies for preventing and/or ameliorating amyloid diseases in the human population. The serious impact of amyloid diseases on populations of domesticated and wild animals is also recognized as an enormous problem for which palliative or curative veterinary pharmaceuticals are desperately needed.